Bioerodible polyorthoesters containing amine groups

ABSTRACT

Bioerodible polyorthoesters useful as orthopedic implants or vehicles for the sustained delivery of pharmaceutical, cosmetic and agricultural agents contain amine functionalities and alpha-hydroxy acid-containing groups.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This application relates to polyorthoesters. In particular, thisinvention relates to bioerodible polyorthoesters containing amine groupsand α-hydroxy acid-containing groups.

2. Description of the Prior Art

Interest in synthetic biodegradable polymers for the systemic deliveryof therapeutic agents began in the early 1970's with the work of Yolleset al., Polymer News 1:9-15 (1970) using poly(lactic acid). Since thattime, numerous other polymers have been prepared and investigated asbioerodible matrices for the controlled release of therapeutic agents.

U.S. Pat. Nos. 4,079,038, 4,093,709, 4,131,648, 4,138,344 and 4,180,646disclose biodegradable or bioerodible polyorthoesters. These polymersare formed by a reaction between an orthoester (or orthocarbonate) suchas 2,2-diethoxytetrahydrofaran and a diol such as1,4-cyclohexanedimethanol. The reaction requires elevated temperatureand reduced pressure and a relatively long reaction time. Drugs or otheractive agents are retained in the polymer matrix to be released as thepolymer biodegrades due to hydrolysis of the labile linkages.

U.S. Pat. No. 4,304,767 discloses polymers prepared by reacting a polyolwith a polyfunctional ketene acetal. These polymers represent asignificant improvement over those of U.S. Pat. Nos. 4,079,038,4,093,709, 4,131,648, 4,138,344 and 4,180,646, since synthesis proceedsreadily at room temperature and atmospheric pressure, and the resultingpolymers have superior properties.

Further polymers are disclosed in U.S. Pat. No. 4,957,998. Thesepolymers contain acetal, carboxy-acetal and carboxy-ortho esterlinkages, and are prepared by a two-step process beginning with thereaction between a polyfunctional ketene acetal and a compoundcontaining a vinyl ether, followed by reaction with a polyol orpolyacid.

Still further polymers of a similar type are disclosed in U.S. Pat. No.4,946,931. The polymers are formed by a reaction between a compoundcontaining a multiplicity of carboxylate functions and a polyfunctionalketene acetal. The resulting polymers have very rapid erosion times.

Despite the ease with which the orthoester linkage hydrolyses,polyorthoesters known in the prior art are extremely stable materialswhen placed in an aqueous buffer, or when residing in the body. Thisstability is attributable to the extreme hydrophobicity of thepolyorthoesters which severely limits the amount of water that canpenetrate the polymer. To achieve useful erosion rates, therefore,acidic excipients must be physically incorporated into the polymer.While this allows control over erosion rates, the physicallyincorporated acidic excipient can diffuse from the polymer matrix atvarying rates, leaving a matrix that is completely depleted of excipientwhile the polymer still has a very long lifetime remaining.

U.S. Pat. Nos. 4,764,364 and 4,855,132 describe bioerodible polymers, inparticular polyorthoesters containing an amine functionality. Thepolymers are said to erode more rapidly at lower pH than at higher pH inan acidic aqueous environment.

The disclosures of the documents listed in this section and elsewherethroughout this application are incorporated herein by reference.

SUMMARY OF THE INVENTION

In a first aspect, this invention is polyorthoesters of formula I orformula II:

R* is a C₁₋₄ alkyl;

R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a is aninteger of 1 to 10, and b and c are independently integers of 1 to 5;

n is an integer of at least 5; and

A is selected from R¹, R², R³, R⁴, and mixtures thereof, where

R¹ is:

where:

p is an integer of 1 to 20;

R⁵ is hydrogen or C₁₋₄ alkyl; and

R⁶is:

where:

s is an integer of 0 to 30;

t is an integer of 2 to 200; and

R⁷ is hydrogen or C₁₋₄ alkyl;

R² is:

 R³is:

where:

x is an integer of 0 to 30;

y is an integer of 2 to 200;

R⁸ is hydrogen or C₁₋₄ alkyl;

R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene;

R¹¹ is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹²together are C₃₋₁₀ alkylene; and

R⁴ is the residual of a diol containing at least one amine functionalityincorporated therein;

in which at least 0.1 mol % of the A units are R¹, and at least 0.1 mol% of the A units are R⁴.

In a second aspect, this invention is controlled release pharmaceuticalcompositions comprising:

(a) an active agent; and

(b) as a vehicle, the polyorthoester described above.

In a third aspect, this invention is a method of treating a diseasestate treatable by controlled release local administration of an activeagent, such as treating pain by administration of a local anesthetic ortreating cancer by administration of a chemotherapeutic orantineoplastic agent, comprising locally administering a therapeuticallyeffective amount of the active agent in the form of the controlledrelease pharmaceutical composition described above.

In a fourth aspect, this invention is methods of preparation of thepolyorthoesters of the first aspect of the invention and the controlledrelease pharmaceutical compositions of the second aspect of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

It has now been discovered that polyorthoesters useful as orthopedicimplants or vehicles for the sequestration and sustained delivery ofdrugs, cosmetic agents and other beneficial agents can be prepared insuch a manner that the rate and degree to which they are hydrolyzed bycontact with bodily fluids at normal body temperature and pH can becontrolled without addition of exogenous acid. This discovery resides inthe incorporation of esters of short-chain α-hydroxy acids such asesters of glycolic acid, lactic acid or glycolic-co-lactic acidcopolymer into the polyorthoester chain and variation of the amount ofthese esters relative to the polyorthoester as a whole.

In the presence of water, these esters, when incorporated into thepolyorthoester chain, are readily hydrolyzed at a body temperature of37° C. and a physiological pH, in particular at a pH of 7.4, to producethe corresponding α-hydroxy acids. The α-hydroxy acids then act as anacidic excipient to control the hydrolysis rate of the polyorthoester.When the polyorthoester is used as a vehicle or matrix entrapping anactive agent, the hydrolysis of the polyorthoester causes release of theactive agent.

The use in these polyorthoesters of diols containing aminefunctionalities causes the polyorthoesters to become more pH-sensitivethan polyorthoesters not containing such diols, and thus to hydrolyzeyet more readily at lower pH than at higher pH. This is particularly soin an acidic aqueous environment, such as is found within animal cells,and enables the polyorthoesters to be relatively stable within theextracellular environment within an animal, such as within the blood,but to hydrolyze rapidly within the intracellular environment. Thismakes these polyorthoesters particularly suitable for delivery of activeagents within the cell.

In addition, the mechano-physical state of the polyorthoester may alsobe controlled. This is achieved by the inclusion of the residues ofcertain diols in selected proportions relative to the polyorthoester asa whole. For example, a high content of the residue of1,4-cyclohexane-dimethanol (as the trans isomer or as a cis/trans isomermixture) or a similar “hard” diol relative to a “soft” diol (definitionof which is given below) produces a relatively rigid polymer chain and amore solid substance, and by decreasing the cyclohexanedimethanolcontent relative to the “soft” diol, the polyorthoester will changeprogressively through the stages of a rigid thermoplastic, a softthermoplastic, a low melting solid to an ointment-like (viscous liquid)material, and any stage in between.

The polyorthoesters of the present invention are prepared bycondensation reactions between diketene acetals and polyols, preferablydiols, and the variation in mechano-physical state and rate ofhydrolysis (bioerodibility) is achieved by the selection and use ofcombinations of different types of diols.

Definitions

“Active agent” includes any compound or mixture of compounds whichproduces a beneficial or useful result. Active agents aredistinguishable from such components as vehicles, carriers, diluents,lubricants, binders and other formulating aids, and encapsulating orotherwise protective components. Examples of active agents arepharmaceutical, agricultural or cosmetic agents. Suitable pharmaceuticalagents include locally or systemically acting pharmaceutically activeagents which may be administered to a subject by topical orintralesional application (including, for example, applying to abradedskin, lacerations, puncture wounds, etc., as well as into surgicalincisions) or by injection, such as subcutaneous, intradermal,intramuscular, intraocular, or intra-articular injection. Examples ofthese agents include, but not limited to, anti-infectives (includingantibiotics, antivirals, fungicides, scabicides or pediculicides),antiseptics (e.g., benzalkonium chloride, benzethonium chloride,chlorhexidine gluconate, mafenide acetate, methylbenzethonium chloride,nitrofurazone, nitromersol and the like), steroids (e.g., estrogens,progestins, androgens, adrenocorticoids, and the like), therapeuticpolypeptides (e.g. insulin, erythropoietin, morphogenic proteins such asbone morphogenic protein, and the like), analgesics andanti-inflammatory agents (e.g., aspirin, ibuprofen, naproxen, ketorolac,COX-1 inhibitors, COX-2 inhibitors, and the like), cancerchemotherapeutic agents (e.g., mechloreihamine, cyclophosphamide,fluorouracil, thioguanine, carmustine, lomustine, melphalan,chlorambucil, streptozocin, methotrexate, vincristine, bleomycin,vinblastine, vindesine, dactinomycin, daunorubicin, doxorubicin,tamoxifen, and the like), narcotics (e.g., morphine, meperidine,codeine, and the like), local anesthetics (e.g., the amide- oranilide-type local anesthetics such as bupivacaine, dibucaine,mepivacaine, procaine, lidocaine, tetracaine, and the like),antiangiogenic agents (e.g., gombrestatin, contortrostatin, anti-VEGF,and the like), polysaccharides, vaccines, antigens, DNA and otherpolynucleotides, antisense oligonucleotides, and the like. The presentinvention may also be applied to other locally acting active agents,such as astringents, antiperspirants, irritants, rubefacients,vesicants, sclerosing agents, caustics, escharotics, keratolytic agents,sunscreens and a variety of dermatologics including hypopigmenting andantipruritic agents. The term “active agents” further includes biocidessuch as fungicides, pesticides, and herbicides, plant growth promotersor inhibitors, preservatives, disinfectants, air purifiers andnutrients.

“Alkyl” denotes a linear saturated hydrocarbyl having from one to thenumber of carbon atoms designated, or a branched or cyclic saturatedhydrocarbyl having from three to the number of carbon atoms designated(e.g., C₁₋₄ alkyl). Examples of alkyl include methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, t-butyl, cyclopropylmethyl, and thelike.

“Alkylene” denotes a branched or unbranched saturated divalent radicalhaving from one to the number of carbon atoms designated (e.g., C₁-C₁₂alkylene). Examples of alkylene include methylene (—CH₂—), ethylene(—CH₂CH₂—), isopentylene (—CH₂—CH(CH₃)—CH₂—CH₂—), n-octylene (—(CH₂)₈—)and the like.

“Bioerodible” and “bioerodibility” refer to the degradation, disassemblyor digestion of the polyorthoester by action of a biologicalenvironment; including the action of living organisms and most notablyat physiological pH and temperature. A principal mechanism forbioerosion of the polyorthoesters of the present invention is hydrolysisof linkages between and within the units of the polyorthoester.

“Comprising” is an inclusive term interpreted to mean containing,embracing, covering or including the elements listed following the term,but not excluding other unrecited elements.

“Controlled release”, “sustained release”, and similar terms are used todenote a mode of active agent delivery that occurs when the active agentis released from the delivery vehicle at an ascertainable andcontrollable rate over a period of time, rather than dispersedimmediately upon application or injection. Controlled or sustainedrelease may extend for hours, days or months, and may vary as a functionof numerous factors. For the pharmaceutical composition of the presentinvention, the rate of release will depend on the type of the excipientselected and the concentration of the excipient in the composition.Another determinant of the rate of release is the rate of hydrolysis ofthe linkages between and within the units of the polyorthoester. Therate of hydrolysis in turn may be controlled by the composition of thepolyorthoester and the number of hydrolyzable bonds in thepolyorthoester. Other factors determining the rate of release of anactive agent from the present pharmaceutical composition includeparticle size, acidity of the medium (either internal or external to thematrix) and physical and chemical properties of the active agent in thematrix.

“Matrix” denotes the physical structure of the polyorthoester whichessentially retains the active agent in a manner preventing release ofthe agent until the polyorthoester erodes or decomposes.

“Sequestration” is the confinement or retention of an active agentwithin the internal spaces of a polyorthoester matrix. Sequestration ofan active agent within the matrix may limit the toxic effect of theagent, prolong the time of action of the agent in a controlled manner,permit the release of the agent in a precisely defined location in anorganism, or protect unstable agents against the action of theenvironment.

A “therapeutically effective amount” means the amount that, whenadministered to an animal for treating a disease, is sufficient toeffect treatment for that disease.

“Treating” or “treatment” of a disease includes preventing the diseasefrom occurring in an animal that may be predisposed to the disease butdoes not yet experience or exhibit symptoms of the disease (prophylactictreatment), inhibiting the disease (slowing or arresting itsdevelopment), providing relief from the symptoms or side-effects of thedisease (including palliative treatment), and relieving the disease(causing regression of the disease). For the purposes of this invention,a “disease” includes pain.

A “unit” denotes an individual segment of a polyorthoester chain, whichconsists of the residue of a diketene acetal molecule and the residue ofa polyol.

An “α-hydroxy acid containing” unit denotes a unit where A is R¹, i.e.in which the polyol is prepared from an α-hydroxy acid or cyclic diesterthereof and a diol of the formula HO—R⁶—OH. The fraction of thepolyorthoester that is α-hydroxy acid containing units affects the rateof hydrolysis (or bioerodibility) of the polyorthoester, and in turn,the release rate of the active agent.

An “amine containing” unit denotes a unit where A is R⁴, i.e. in whichthe diol contains an amine functionality. The fraction of thepolyorthoester that is amine containing units affects the pH-sensitivityof the rate of hydrolysis (or bioerodibility) of the polyorthoester, andin turn, the release rate of the active agent.

“Hard” and “soft” units denote individual units of the polyorthoester,the contents of which relative to the polyorthoester as a wholedetermine the mechano-physical state of the polyorthoester. “Hard” unitsare units where A is R² and “soft” units are units where A is R³.

“Vehicle” and “carrier” denote an ingredient that is included in acomposition such as a pharmaceutical or cosmetic preparation for reasonsother than a therapeutic or other biological effect. Functions served byvehicles and carriers include transporting an active agent to a site ofinterest, controlling the rate of access to, or release of, the activeagent by sequestration or other means, and facilitating the applicationof the agent to the region where its activity is needed. Examples ofvehicles and carriers include solids such as microparticles,microspheres, rods, and wafers; and semisolids that are dispensable bysyringe or the like, or by spreading with a tool such as a spatula.

The polyorthoesters

The polyorthoesters are of formula I or formula II

R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a is aninteger of 1 to 10, and b and c are independently integers of 1 to 5;

n is an integer of at least 5; and

A is selected from R¹, R² R³, R⁴, and mixtures thereof, where

R¹ is:

where:

P is an integer of 1 to 20;

R⁵ is hydrogen or C₁₋₄ alkyl; and

R⁶ is:

where:

s is an integer of 0 to 30;

t is an integer of 2 to 200; and

R⁷ is hydrogen or C₁₋₄ alkyl;

R² is:

R³ is:

where:

x is an integer of 0 to 30;

y is an integer of 2 to 200;

R⁸ is hydrogen or C₁₋₄ alkyl;

R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene;

R¹¹ is hydrogen or C₁₋₁₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹²together are C₃₋₁₀ alkylene; and

R⁴ is the residual of a diol containing at least one amine functionalityincorporated therein; in which at least 0.1 mol % of the A units are R¹,and at least 0.1 mol % of the A units are R⁴.

The structure of the polyorthoester useful for the present invention, asshown in formula I or formula II, is one of alternating residues of adiketene acetal and a diol, with each adjacent pair of diketene acetalresidues being separated by the residue of one polyol, preferably adiol.

In the presence of water, the x-hydroxyacid containing units are readilyhydrolyzed at a body temperature of 37° C. and a physiological pH, toproduce the corresponding hydroxyacids. These hydroxyacids then act asacidic catalysts to control the hydrolysis rate of the polyorthoesterwithout the addition of exogenous acid. When the polyorthoester is usedas a delivery vehicle or matrix entrapping an active agent, thehydrolysis of the polyorthoester causes release of the active agent.

Polyorthoesters having a higher mole percentage of the “α-hydroxy acidcontaining” units will have a higher rate of bioerodibility. Preferredpolyorthoesters are those in which the mole percentage of the “α-hydroxyacid containing” units is in the range of about 0.1 to about 99 molepercent, such as about 0.5 to about 50 mole percent, more preferablyfrom about 1 to about 30 mole percent, for example from about 5 to about30 mole percent, especially from about 10 to about 30 mole percent.

Polyorthoesters having a higher mole percentage of the “aminecontaining” units will have a rate of bioerodibility that is morepH-sensitive than non-“amine containing” polyorthoesters, and increasesat lower pH. Preferred polyorthoesters are those in which the molepercentage of the “amine containing” units is in the range of about 0.1to about 99.9 mole percent, more preferably from about 1 to about 80mole percent, for example from about 5 to about 50 mole percent,especially from about 10 to about 30 mole percent.

Preferred polyorthoesters are those where:

n is an integer of about 5 to about 500, preferably about 20 to about500, especially about 30 to about 300;

R⁵ is hydrogen or methyl;

R⁶ is:

 where s is an integer of 0 to 10, especially 1 to 4; t is an integer of2 to 30, especially 2 to 10; and

R⁷ is hydrogen or methyl;

R³ is:

 where x is an integer of 0 to 10, especially 1 to 4; y is an integer of2 to 30, especially 2 to 10; and

R⁸ is hydrogen or methyl;

R⁴ is selected from the residue (i.e. that part of the diol that is notthe two hydroxy groups) of aliphatic diols of 2 to 20 carbon atoms,preferably 2 to 10 carbon atoms, interrupted by one or two amine groups,or is selected from the residue of di(hydroxy)- orbis(hydroxyalkyl)-cyclic amines, having from 4 to 20, preferably 4 to10, carbon or nitrogen atoms between the hydroxy groups;

the amine groups are secondary or, preferably, tertiary amine groups;

the proportion of units in which A is R¹ is about 0.5 to about 50 molepercent, more preferably from about 1 to about 30 mole percent, forexample from about 5 to about 30 mole percent, especially from about 10to about 30 mole percent; and

the proportion of units in which A is R⁴ is about 1 to about 80 molepercent, for example from about 5 to about 50 mole percent, especiallyfrom about 10 to about 30 mole percent.

While the presence of any of these preferences results in apolyorthoester that is more preferred than the same polyorthoester inwhich the preference is not met, the preferences are generallyindependent, and polyorthoesters in which a greater number ofpreferences is met will generally result in a polyorthoester that ismore preferred than that in which a lesser number of preferences is met.

Expressed in terms of mole percent of the “hard” unit relative to thepolyorthoester as a whole, preferred polyorthoesters for liquid orsemi-solid compositions are those in which the “hard” unit constitutesabout 20 mole percent or less. Likewise, preferred polyorthoesters formore solid compositions are those in which the “hard” unit constitutesfrom about 30 mole percent to about 99.8 mole percent.

Polyorthoesters having a higher content of the “α-hydroxy acidcontaining” unit will have a higher rate of bioerodibility.

With respect to the individual “α-hydroxy acid containing” unit, p ispreferably 1 to 6, more preferably 1 to 4, most preferably 1 or 2; R⁵ ispreferably hydrogen or methyl; and in the above definitions of R⁶, s ispreferably 2 to 12, more preferably 2 to 6 and most preferably 2; and tis preferably 4 to 12, more preferably 4 to 6 and most preferably 6.

With respect to the individual “hard” unit, R² is preferablycyclohexanedimethanol.

With respect to the individual “soft” unit, in the definitions of R³, xis preferably 2 to 12, more preferably 2 to 6 and most preferably 2; yis preferably 4 to 12, more preferably 4 to 6 and most preferably 6; R⁸is preferably hydrogen; R⁹ is preferably methyl; R¹⁰ is preferablyhydrogen and R¹¹ is preferably methyl.

With respect to the individual “amine containing” unit, diols of theformula HO—R⁴—OH include aliphatic diols of 2 to 20 carbon atoms,preferably 2 to 10 carbon atoms, interrupted by one or two amine groups,and di(hydroxy)- or bis(hydroxyalkyl)-cyclic amines, having from 4 to20, preferably 4 to 10, carbon or nitrogen atoms between the hydroxygroups; and the amine groups are secondary or, preferably, tertiary,amine groups.

Preparation of the Polyorthoesters

The polyorthoesters are prepared according to the methods described inU.S. Pat. Nos. 4,764,364, 4,855,132, and 5,968,543. Specifically, thepolyorthoesters are prepared by the reaction of a diketene acetal offormula III or formula IV:

where L is hydrogen or a C₁₋₃ alkyl, with a diol of the formula HO—R¹—OHand a diol of the formula HO—R⁴—OH, and optionally at least one diol ofthe formulae HO—R²—OH and HO—R³—OH.

To form the polyorthoester using a mixture of the various types of thediols, the mixture is formed with selected proportions based on thedesired characteristics of the polyorthoester. The use of increasingamounts of diols in which A is R¹ increases the bioerodibility of thepolyorthoester, and the use of such diols in which R⁶ is apolyethyleneoxide moiety or an alkane increases the softness of thepolymer; the use of increasing amounts of diols in which A is R²increases the hardness of the polyorthoester; and the use of diols inwhich A is R³ increases the softness of the polyorthoester, especiallywhen these diols are low molecular weight polyethylene glycols oraliphatic diols. The use of diols in which A is R⁴ increases thepH-sensitivity of the bioerodibility of the polyorthoester, increasingit particularly at low pH.

The preparation of the diketene acetals of the types of formula III andformula IV is disclosed in U.S. Pat. Nos. 4,304,767, 4,532,335, and5,968,543; and will be known to a person of ordinary skill in the art. Atypical method is the condensation of a bis(diol) of formula V (i.e.pentaerythritol) or formula VI:

with two equivalents of a 2-halocarboxaldehyde dialkyl acetal, such as2-bromoacetaldehyde diethyl acetal, followed by dehydrohalogenation togive the diketene acetal. The condensation of a glycol withdiethylbromoacetals is described in Roberts et al., J. Am. Chem. Soc.,80, 1247-1254 (1958), and dehydrohalogenation is described in Beyerstedtet al., J. Am. Chem. Soc., 58, 529-553 (1936).

The diketene acetals may also be prepared by the isomerization ofdivinyl acetals. Thus, for example,3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU) may beprepared by the isomerization of3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]undecane, using n-butyllithium inethylenediamine. The isomerization of the double bond is described inCorey et al., J. Org. Chem., 38, 3224 (1973). The divinyl acetals may beprepared by the condensation of the bis(diol) of formula V or formula VIwith two equivalents of a vinylic aldehyde, such as acrolein orcrotonaldehyde, or their dialkyl acetals, such as acrolein dimethylacetal, and such condensation reactions are well known.

The bis(diol) of formula VI where R is a bond is erytiritol. Thebis(diol) of formula VI where R is —(CH₂)_(a)—may be prepared by theoxidation of an α,ω-diene, such as 1,3-butadiene or 1,5-hexadiene, withan oxidizing reagent such as osmium tetroxide/hydrogen peroxide, or byother methods known in the art, to give the bis(diol). The bis(diol) offormula VI where R is —(CH₂)_(b)—O—(CH₂)_(c)— may be prepared by thereaction of an ω-hydroxy-α-olefin, such as allyl alcohol, with anω-haloalkyloxirane, such as epichlorohydrin, to form an ω-epoxy-α-olefinwith the backbone interrupted by an oxygen atom, such as2-allyloxymethyloxirane, which is then oxidized with an oxidizingreagent such as osmium tetroxide/hydrogen peroxide, or by other methodsknown in the art, to give the bis(diol).

The rigidity or flexibility of the polyorthoester is determined by theproportions of the “hard” units and “soft” units in the polyorthoesterstructure, with greater rigidity achieved by including greaterproportions of the “hard” units in the polyorthoester.

The bioerodibility of the polyorthoester is determined by the proportionof the hydrolyzable α-hydroxy acid ester groups, with greaterbioerodibility achieved by including greater proportions of the“α-hydroxy acid containing” units. The pH sensitivity of thebioerodibility is increased by the proportion of “amine containing”units, with a greater proportion making the material more rapidlybioerodible at low pH.

Thus, both characteristics of the resulting polyorthoester prepared fromthe reaction between the diketene acetal of Formula III or formula IVand a mixture of the diols, are controlled by the ratio of quantities ofthe two to four types of diols in the diol mixture.

It is also understood that the present invention also encompassescross-linked polyorthoesters which are prepared by employing one or morepolyols having more than two hydroxy functional groups. Suchcross-linked polyorthoesters may be prepared preferably by firstreacting the diketene acetal with a diol in which A is R¹, R², R³, R⁴,or a mixture thereof, followed by addition of the polyol(s) having morethan two hydroxy functional groups. Alternatively, the polyol(s) havingmore than two hydroxy functional groups may be added simultaneously withthe diols. Polyols having more than two hydroxy functional groupssuitable for the preparation of the cross-linked polyorthoesters may bethe straight or branched chain type, including polyhydroxyl compoundssuch as 1,2,3-propanetriol, 1,2,5-pentanetriol, 1,2,6-hexanetriol,1,3,5-pentanetriol, 1,2,4-butanetriol, 1,4,7-heptanetriol,1,5,10-decanetriol, 1,5,12-dodecanetriol, 1,2,3,4,5,6-hexane-hexol, orsuch arnine-containing polyhydroxyl compounds astris(2-hydroxyethyl)amine and the like. Other representative polyols ofthe type are described in U.S. Pat. No. 4,304,767. The reactionconditions (e.g, suitable solvents and reaction temperatures) andprocedures for the preparation of the cross-linked polyorthoesters aresimilar to those described above for the preparation of thepolyorthoesters employing only the diols, and are also described in U.S.Pat. Nos. 4,304,767 and 5,968,543.

The preparation of diols, in particular the diol of the formula HO—R³—OHis generally disclosed in Heller et al., J. Polymer Sci., PolymerLetters Ed. 18:293-297 (1980), by reacting an appropriate divinyl etherwith an excess of an appropriate diol.

Diols of the formula HO—R⁴—OH are diols containing at least onesecondary or, preferably, tertiary amine. They include diols where R⁴ isan amine such as R′NR″R′″ or R′N═R′″ where each of R′ and R′″ isindependently an aliphatic, aromatic, or aromatic/aliphatic straight orbranched chain hydrocarbyl to which is bonded one of the hydroxy groupsof the diol, and optionally where R′ and R′″ are bonded so that theamine is a cyclic amine, especially a straight or branched chain alkylof 2 to 10 carbon atoms, and more especially 2 to 5 carbon atoms, and R″is hydrogen, C₁₋₆ alkyl, C₆₋₁₀ aryl, or aralkyl, especially alkyl, andmore especially methyl. Other diols include those where two such aminegroups are present, including in the same cyclic amine. Thusrepresentative cyclic amine-based diols of the formula HO—R⁴—OH includedi(hydroxy)- or bis(hydroxyalkyl)-substituted cyclic amines such assubstituted pyridine, piperidine, pyridazine, pyrimidine, pyrazine,piperazine, and the like. Some representative diols of the formulaHO—R⁴—OH include N,N-bis(2-hydroxyethyl)amine,N,N-bis(2-hydroxyethyl)aniline, N-methyl-N,N-bis(2-hydroxyethyl)amine,N-butyl-N,N-bis(2-hydroxyethyl)amine,N-propyl-N,N-bis(2-hydroxyethyl)amine,N-2-propyl-N,N-bis(2-hydroxyethyl)amine,N-cyclohexyl-N,N-bis(2-hydroxyethyl)amine,N-benzyl-N,N-bis(2-hydroxyethyl)amine, 3-dimethylamino-1,2-propanediol,3-(tert-butylamino)-1,2-propanediol, 1,4-bis(2-hydroxyethyl)piperidine,1,4-bis(2-hydroxyethyl)piperazine, 1,4-bis(hydroxymethyl)piperazine,7-(2,3 -dihydroxy-propyl)theophylline, 3,6-dihydroxypyridazine,2,3-dihydroxypyridine, 2,4-dihydroxypyridine, 2,6-dihydroxypyridine,4,6-dihydroxypyrimidine, N-ethyl-N,N-bis(2-hydroxyethyl)amine, and thelike. Such diols include those containing both secondary and tertiaryamines, though tertiary amines are preferred. Amine-containing polyolsinclude N-3-hydroxypropyl-N,N-bis(2-hydroxyethyl)amine,1,3-bis[tris(hydroxymethyl)methylamino]propane,2,2-bis(hydroxymethyl)-2,2′,2″-nitrilotriethanol,tris(2-hydroxyethyl)amine, tris(3-hydroxypropyl)amine, and the like.These diols are known to the art in reported syntheses and many arecommercially available.

Once made, the diol of the formula HO—R¹—OH and the diol of the formulaHO—R⁴—OH, and the optional diol(s) of the formulae HO—R²—OH and HO—R³—OHin the desired proportions are mixed with the diketene acetal of formulaIII or formula IV, in an approximately 1:1 ratio of total number ofmoles of diketene acetal to total number of moles of diols, in asuitable solvent at ambient temperature. The condensation reactionbetween the diketene acetal and the diols is carried out underconditions which are described in, for example, U.S. Pat. Nos.4,764,364, 4,855,132, and 5,986,543, and are well known to those skilledin the art; and will also be readily apparent from the structures of thereactants themselves. Suitable solvents are aprotic solvents, such asdimethylacetamide, dimethyl sulfoxide, dimethylformamide, acetonitrile,acetone, ethyl acetate, pyrrolidone, tetrahydrofuran, and methylbutylether, and the like. Catalysts are not required for this reaction, butwhen used, suitable catalysts are iodine in pyridine, p-toluenesulfonicacid; salicylic acid, Lewis acids (such as boron trichloride, borontrifluoride, boron trichloride etherate, boron trifluoride etherate,stannic oxychloride, phosphorous oxychloride, zinc chloride, phosphoruspentachloride, antimony pentafluoride, stannous octoate, stannicchloride, diethyl zinc, and mixtures thereof); and Brønsted catalysts(such as polyphosphoric acid, crosslinked polystyrene sulfonic acid,acidic silica gel, and mixtures thereof). A typical amount of catalystused is about 0.2% by weight relative to the diketene acetal. Smaller orlarger amounts can also be used, such as 0.005% to about 2.0% by weightrelative to the diketene acetal. Once the reaction is complete, thereaction mixture is allowed to cool and concentrated by rotoevaporationunder vacuum, for a semi-solid polyorthoester; or by precipitation in anon-solvent such as an alkanol (e.g. methanol, ethanol, and the like) oran alkane (e.g. hexanes, heptanes, and the like), for a solidpolyorthoester. The polyorthoester may be further dried under vacuum atan elevated temperature.

The polyorthoesters may also be prepared by reaction of the diketeneacetal with the chosen diol(s) under similar reaction conditions, but inthe presence of a “chain stopper” (a reagent that terminatespolyorthoester chain formation. Suitable chain stoppers are C₅₋₂₀alkanols, especially C₁₀₋₂₀ alkanols. The chain stopper is preferablypresent in from 1-20 mol % based on the diketene acetal. Thepolyorthoesters thus prepared have lower molecular weights with a lowermolecular weight dispersion than those prepared by the reaction of thediketene acetals with only diols.

The invention includes polyorthoesters which contain all four types ofunits as well as polyorthoesters containing from only the “α-hydroxyacid containing” units and “amide containing” units, or a mixture ofthese units with only one of the “hard” units or “soft” units. It alsoincludes polyorthoesters prepared from a mixture of units which containstwo or more diols of the same type. It further includes polyorthoesterscontaining triols or higher polyols and/or “chain stopper”mono-alcohols, as described above.

Uses of the Polyorthoesters

The present polyorthoesters can be used for any use in which bioerodiblepolymers are usable, such as vehicles for the sustained release of anactive agent.

To use the polyorthoester as a sustained-release vehicle or carrier, theactive agent must be incorporated into a matrix of the polyorthoester orencapsulated within a capsule (or a “microcapsule” or “nanocapsule”, asthose terms are sometimes used) of the polyorthoester. Methods for thepreparation of sustained-release dosage forms using biodegradablepolymers are well known in the art, as discussed in the references citedin the “Description of the Prior Art” section of this application, andin other references familiar to those of ordinary skill in the art; sothat a person of ordinary skill in the art would have no difficulty,having regard to that skill and this disclosure, in preparingsustained-release formulations using the polyorthoester of thisinvention. Suitable active agents include therapeutic agents such aspharmaceutical or pharmacological active agents, e.g. drugs andmedicaments, as well as prophylactic agents, diagnostic agents, andother chemicals or materials useful in preventing or treating disease.The compositions of this invention are particularly useful for thetherapeutic treatment of humans and other mammals, but may also be usedfor other animals. In addition, the sustained-release compositions ofthis invention may also be used for the release of cosmetic andagricultural agents, or for the release of biocides, such as fungicidesor other pesticides, into an environment where prolonged release of theactive agent is desired.

In the case of matrix formulations, the polyorthoester is first mixedwith the active agent. High homogeneity may be achieved by mixing thepolyorthoester in its heat softened state with the active agent,followed by lowering the temperature to harden the composition.Alternatively, the polyorthoester can be dissolved in an appropriatecasting solvent, such as tetrahydrofuran, methylene chloride, chloroformor ethyl acetate, and the active agent can then be dispersed ordissolved in the polyorthoester solution, followed by evaporating thesolvent to achieve the finished composition. Another method is grindinga solid polyorthoester material into powder which is then mixed with apowdered active agent. The active agent may also be incorporated intothe mixture of monomers before polymerization provided that it is stableunder the polymerization conditions and does not interfere with thepolymerization reaction.

If the active agent is one that is unstable at elevated temperatures(e.g. above 40° C.), or in the presence of organic solvents or organicsolvent/water mixtures, such as a protein, then special preparationtechniques may be required to minimize the exposure of the active agentto damaging conditions. Such techniques are disclosed in, for example,U.S. Pat. No. 5,620,697 (Törmälä et al., assigned to Orion-Yhtyma Oy andLeiras Oy), which discloses ultrasonic melting to form matrix-typepharmaceutical compositions, and U.S. Pat. No. 5,518,730 (Fuisz,assigned to Fuisz Technologies, Inc.), which discloses melt-spinning,both of which techniques are designed to minimize the exposure of thepolymer and active to elevated temperatures. Other methods are disclosedin the patents and literature references cited elsewhere in thisapplication.

An alternate method for the incorporation and release of sensitivetherapeutic agents is to use bioerodible polyorthoesters that havephysical properties tailored for this incorporation. For example, thepolyorthoester may be chosen so that it is semi-solid and has anointment-like consistency, rather than being fully solid.

The composition obtained from any of the above methods can be readilyprocessed into a variety of shapes and forms for implantation, insertionor placement on the body or into body cavities or passageways. Forexample, the polyorthoester composition may be injection molded,extruded or compressed into a thin film or made into devices of variousgeometric shapes or forms such as flat, square, round, cylindrical,tubular, disc, ring and the like. Rod- or pellet-shaped devices may beimplanted through a trocar, such as is known for Norplant® implants, andthese or other shapes may be implanted by minor surgical procedures.Alternatively, a device may be implanted following a major surgicalprocedure such as tumor removal in the surgical treatment of cancer.

The polyorthoester composition may also be injected by syringesubcutaneously or intramuscularly as particles of 0.1 μm to 1000 μm,preferably 0.5 μm to 200 μm, and more preferably 1 μm to 150 μmsuspended in a pharmaceutically acceptable injection base. Liquidvehicles useful for suspending the drug-polyorthoester composition forinjection include isotonic saline solution or oils (such as corn oil,cottonseed oil, peanut oil and sesame oil) which, if desired, maycontain other adjuvants.

Another injectable dosage form may be prepared from an active agentmixed in a polyorthoester of the present invention which has ansemi-solid consistency or which, when mixed with a suitable liquidexcipient, forms a semi-solid composition such as the compositionsdescribed in U.S. patent application Ser. No. 09/854,180. Such a dosageform may be administered by injection. Such a dosage form may also beadministered by direct application to an area to be treated, such as byspreading into a wound with a spatula.

The polyorthoester composition administered by either injection orimplantation undergoes bioerosion in the body into non-toxic andnon-reactive materials. By controlling the number of hydrolyzable bondsin the polyorthoester, the active agent may be released at a desiredrate. Implants prepared from the present polyorthoesters in which thepolyorthoester constitutes the matrix containing an active agent alsohave the advantage that they do not require removal because of thebioerodibility of the polyorthoester.

In some cases, particles with cores of the pure active agent coated withvarious thicknesses of the present polyorthoester may be preferred forsustained delivery of the active agent. Coating or encapsulation ofdiscrete particles of the active agent may be accomplished byconventional methods which are all well-known to the person skilled inthe art. For example, finely divided drug particles may be suspended ina solvent system (in which the drug is not soluble) containing thedissolved polyorthoester and other excipients, followed by spray drying.Alternatively, the drug particles may be placed in a rotating pan or afluid-bed dryer and the polyorthoester dissolved in a carrier solvent issprayed onto the drug particles until a suitable coating quantity isdeposited on the particles to give a desired thickness. The coating mayalso be achieved by suspending the drug particles in a solvent systemcontaining the dissolved polyorthoester followed by adding to thesuspension a non-solvent causing the polyorthoester to precipitate andform a coating over the drug particles.

For the sustained release compositions, because the active agent will bereleased over a controlled period of time, the agent usually is presentin an amount which is greater than the conventional single dose. Therelative proportions of the active agent and the polyorthoester can varyover a wide range (e.g., 0.1 to 50 weight percent) depending on thetherapeutic agent and the desired effect.

Sustained compositions of cosmetic and agricultural agents may also beprepared by any one of the methods as described above, using thepolyorthoesters of the present invention.

The solid polyorthoesters (those containing a high percentage of the“hard” unit and/or a high proportion of the “hydrogen bonding” unit) arealso useful for a variety of orthopedic applications. For example, theycan be used as fracture fixation devices for repair of osteochondraldefects, ligament and tendon reconstructions and bone substitutes. Inaddition, the fact that the present polyorthoesters permit simultaneousselection of both a desired level of their mechano-physical state and adesired rate of bioerodibility, also renders them attractive as graftsor scaffolds on which cells can be cultured in vitro prior toimplantation to regenerate tissues. Tissues which can be regeneratedusing this approach include but not limited to, bone, tendon, cartilage,ligaments, liver, intestine, ureter and skin tissues. For example, thepolyorthoesters may be used to regenerate skin for patients with bums orskin ulcers. Cartilages may be repaired by first isolating chondrocytesfrom a patient (or a donor), allowing them to proliferate on thescaffolds prepared from the present polyorthoester and re-implanting thecells in the patient.

The polyorthoester scaffolds or implants may further contain otherbiologically active substances or synthetic inorganic materials such asreinforcing filler material for enhancing the mechanical properties ofthe scaffolds or implants (e.g. calcium sodium metaphosphate fibers),antibiotics or bone growth factors to induce and/or promote orthopedicrestoration and tissue regeneration.

The compositions are also stable. The release rates of the active agentare not significantly affected by irradiation for sterilization.

Particular Compositions and their Uses

Exemplary compositions of this invention, and their uses, include:

(1) compositions containing local anesthetics, optionally in combinationwith glucocorticosteroids such as dexamethasone, cortisone,hydrocortisone, prednisone, prednisolone, beclomethasone, betamethasone,flunisolide, fluoconolone acetonide, fluocinonide, triamcinolone, andthe like, for the prolonged relief of local pain or a prolonged nerveblockade;

(2) compositions containing cancer chemotherapeutic agents, such asthose listed above under “Active Agents”, for deposition by syringe orby injection into tumors or operative sites from which a tumor has beenablated, for tumor control or treatment and/or the suppression ofregrowth of the tumor from residual tumor cells after ablation of thetumor;

(3) compositions containing progestogens, such as flurogestone,medroxyprogesterone, norgestrel, norgestimate, norethindrone, and thelike, for estrus synchronization or contraception;

(4) compositions containing antimetabolites such as fluorouracil and thelike, as an adjunct to glaucoma filtering surgery; compositionscontaining antiangiogenic agents such as combrestatin, for the treatmentof macular degeneration and retinal angiogenesis; and other compositionsfor the controlled release of ophthalmic drugs to the eye;

(5) compositions containing therapeutic polypeptides (proteins), such asinsulin, LHRH antagonists, and the like, for the controlled delivery ofthese polypeptides, avoiding the need for daily or other frequentinjection;

(6) compositions containing anti-inflammatory agents such as the NSAIDs,e.g. ibuprofen, naproxen, COX- 1 or COX-2 inhibitors, and the like, orglucocorticosteroids, for intra-articular injection;

(7) compositions containing antibiotics, for the prevention or treatmentof infection, especially for deposition into surgical sites to suppresspost-operative infection, or into or on wounds, for the suppression ofinfection (e.g. from foreign bodies in the wound);

(8) compositions containing morphogenic proteins such as bonemorphogenic protein; and

(9) compositions containing DNA or other polynucleotides, such asantisense oligonucleotides.

EXAMPLES

The following syntheses illustrate the preparation of polyorthoesters ofthis invention.

Example 1

In a dry box, 8.639 g (40 mmol) of3,9-diethylidene-2,4,8,10-tetraoxa-spiro[5.5]undecane (DETOSU) wasweighed into a round-bottomed flask. 2.019 g (14 mmol) oftrans-cyclohexanedimethanol (CDM), 1.668 g (14 mmol) ofN-methyldiethanolamine (MDEA) and 1.502 g (10 mmol) of triethyleneglycol (TEG) were weighed and added to the DETOSU solution with the aidof 23 mL of tetrahydrofuran (THF) in several portions. Separately, 0.416g (2 mmol) of triethylene glycol monoglycolide (TEG-mGL) was weighedinto a vial and dissolved in 2 mL THF. Both containers were sealed andremoved from the dry box. The reaction flask was rapidly connected to acondenser and a nitrogen inlet. The TEG-mGL solution was added to thereaction mixture, and 100 μL of iodine in pyridine (500 μg/μL) was addedwith a Hamilton syringe at a rate of 1 drop/10 seconds. After thereaction exotherm subsided, the reaction mixture was diluted with 36 mlof THF, and slowly dropped into 500 mL of methanol containing 1000 ppmof triethylamine. The polymer was isolated by decanting the solvent, anddried in a vacuum oven at 90° C. for 6 hours. The polyorthoester had anM_(w) (weight average molecular weight) of 44,900, and an M_(n) (numberaverage molecular weight) of 23,600.

Example 2

In a dry box, 8.639 g (40 mmol) of DETOSU was weighed into around-bottomed flask. 2.019 g (14 mmol) of CDM, 2.383 g (20 mmol) ofMDEA, and 0.601 g (4 mmol) of TEG were weighed and added to the DETOSUsolution with the aid of 23 mL of THF in several portions. Separately,0.416 g (2 mmol) of TEG-mGL was weighed into a vial and dissolved in 2mL THF. Both containers were sealed and removed from the dry box. Thereaction flask was rapidly connected to a condenser and a nitrogeninlet. The TEG-mGL solution was added to the reaction mixture, and 100μL of iodine in pyridine (500 μg/μL) was added with a Hamilton syringeat a rate of 1 drop/10 seconds. After the reaction exotherm subsided,the reaction mixture was diluted with 36 mL of THF, and slowly droppedinto 500 mL of methanol containing 1000 ppm of triethylamine. Thepolymer was isolated by decanting the solvent, and dried in a vacuumoven at 90° C. for 6 hours. The polyorthoester had an M_(w) of 47,600,and an M_(n) of 26,400.

Example 3

In a dry box, 8.639 g (40 mmol) of DETOSU was weighed into around-bottomed flask. 2.019 g (14 mmol) of CDM, 1.668 g (14 mmol) ofMDEA, 0.901 g (6 mmol) of TEG, and 0.304 g (4 mmol) of 1,2-propanediolwere weighed and added to the DETOSU solution with the aid of 23 mL ofTHF in several portions. Separately, 0.416 g (2 mmol) of TEG-mGL wasweighed into a vial and dissolved in 2 mL THF. Both containers weresealed and removed from the dry box. The reaction flask was rapidlyconnected to a condenser and a nitrogen inlet. The TEG-mGL solution wasadded to the reaction mixture, and 100 μL of iodine in pyridine (500μg/μL) was added with a Hamilton syringe at a rate of 1 drop/10 seconds.After the reaction exotherm subsided, the reaction mixture was dilutedwith 36 mL of THF, and slowly dropped into 500 mL of methanol containing1000 ppm of triethylamine. The polymer was isolated by decanting thesolvent, and dried in a vacuum oven at 90° C. for 6 hours. Thepolyorthoester had an M_(w) of 44,300, and an M_(n) of 24,600.

The foregoing is offered primarily for purposes of illustration. It willbe readily apparent to those skilled in the art that the molecularstructures, proportions of the reactant materials, methods of use andother parameters of the invention described herein may be furthermodified or substituted in various ways without departing from thespirit and scope of the invention.

What is claimed is:
 1. A polyorthoester of formula I or formula II:

where: R* is a C₁₋₄ alkyl; R is a bond, —(CH₂)_(a)—, or—(CH₂)_(b)—O—(CH₂)_(c)—; where a is an integer of 1 to 10, and b and care independently integers of 1 to 5; n is an integer of at least 5; andA is a mixture of R¹ and R⁴, and optionally R² and or R³, where R¹ is:

where: p is an integer of 1 to 20; R⁵ is hydrogen or C₁₋₄ alkyl; and R⁶is:

where: s is an integer of 0 to 30; t is an integer of 2 to 200; and R⁷ishydrogen or C₁₋₄ alkyl; R² is:

 R³ is:

where: x is an integer of 0 to 30; y is an integer of 2 to 200; R⁸ ishydrogen or C₁₋₄ alkyl; R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene; R¹¹is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹² togetherare C₃₋₁₀ alkylene; and R⁴ is the residual of a diol containing at leastone amine functionality incorporated therein; in which at least 0.1 mol% of the A units are R¹, and at least 0.1 mol % of the A units are R⁴.2. The polyorthoester of claim 1 where n is about 5 to about
 500. 3. Thepolyorthoester of claim 2 where n is about 20 to about
 500. 4. Thepolyorthoester of claim 3 where n is about 30 to about
 300. 5. Thepolyorthoester of claim 1 which comprises about 0.5 to about 50 molepercent of units in which A is R¹.
 6. The polyorthoester of claim 5which, comprises about 1 to about 30 mole percent of units in which A isR¹.
 7. The polyorthoester of claim 6 which comprises about 5 to about 30mole percent of units in which A is R¹.
 8. The polyorthoester of claim 7which comprises about 10 to about 30 mole percent of units in which A isR¹.
 9. The polyorthoester of claim 1 where p is 1 to
 6. 10. Thepolyorthoester of claim 9 where p is 1 to
 4. 11. The polyorthoester ofclaim 10 where p is 1 to
 2. 12. The polyorthoester of claim 1 where R⁵is hydrogen or methyl.
 13. The polyorthoester of claim 1 which comprisesabout 1 to about 80 mole percent of units in which A is R⁴.
 14. Thepolyorthoester of claim 13 which comprises about 5 to about 50 molepercent of units in which A is R⁴.
 15. A process of preparing apolyorthoester of formula I or formula II:

where: R* is a C₁₋₄ alkyl; R is a bond, —(CH₂)_(a)—, or—(CH₂)_(b)—O—(CH₂)_(c)—; where a is an integer of 1 to 10, and b and care independently integers of 1 to 5; n is an integer of at least 5; andA is a mixture of R¹ and R⁴, and optionally R² and/or R³, where R¹ is:

where: p is an integer of 1 to 20; R⁵ is hydrogen or C₁₋₄ alkyl; and R⁶is:

where: s is an integer of 0 to 30; t is an integer of 2 to 200; and R⁷is hydrogen or C₁₋₄ alkyl; R² is:

 R³ is:

where: x is an integer of 0 to 30; y is an integer of 2 to 200; R⁸ ishydrogen or C₁₋₄ alkyl; R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene; R¹¹is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹² togetherare C₃₋₁₀ alkylene; and R⁴ is the residual of a diol containing at leastone amine functionality incorporated therein; in which at least 0.1 mol% of the A units are R¹, and at least 0.1 mol % of the A units are R⁴,the process comprising reacting a diketene acetal of formula III orformula IV:

where R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a isan integer of 1 to 10, and b and c are independently integers of 1 to 5;L is hydrogen or a C₁₋₃ alkyl; with a diol of the formula HO—R¹—OH and adiol of the formula HO—R⁴—OH, and optionally at least one diol of theformulae HO—R²—OH and HO—R³—OH.
 16. A polyorthoester that is the productof a reaction between: (a) a diketene acetal of formula III or formulaIV:

where R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a isan integer of 1 to 10, and b and c are independently integers of 1 to 5;L is hydrogen or a C₁₋₃ alkyl, and (b) a polyol or mixture of polyols inwhich at least 0.1 mole percent of the total polyol content is a diol ofthe formula HO—R¹—OH, where R¹ is:

where: p is an integer of 1 to 20; R⁵ is hydrogen or C₁₋₄ alkyl; and R⁶is:

where: s is an integer of 0 to 30; t is an integer of 2 to 200; and R⁷is hydrogen or C₁₋₄ alkyl; R¹¹ is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆alkyl; or R¹¹ and R¹² together are C₃₋₁₀ alkylene; and at least 0.1 molepercent of the total polyol content is a diol of the formula HO—R⁴—OH,where R⁴ is the residual of a diol containing at least one aminefunctionality incorporated therein.
 17. The polyorthoester of claim 18where at least one of the polyols is a polyol having more than twohydroxy functional groups.
 18. A device for orthopedic restoration ortissue regeneration comprising a polyorthoester of claim
 1. 19. Apharmaceutical composition comprising: (a) an active agent; and (b) as avehicle, the polyorthoester of claim
 1. 20. The pharmaceuticalcomposition of claim 19 where the fraction of the active agent is from1% to 60% by weight of the composition.
 21. The pharmaceuticalcomposition of claim 20 where the fraction of the active agent is from5% to 30% by weight of the composition.
 22. The pharmaceuticalcomposition of claim 19 where the active agent is selected fromanti-infectives, antiseptics, steroids, therapeutic polypeptides,anti-inflammatory agents, cancer chemotherapeutic agents, narcotics,local anesthetics, antiangiogenic agents, vaccines, antigens, DNA, andantisense oligonucleotides.
 23. The pharmaceutical composition of claim19 where the active agent is a therapeutic polypeptide.
 24. Thepharmaceutical composition of claim 19 where the active agent is a localanesthetic.
 25. The pharmaceutical composition of claim 24 furthercomprising a glucocorticosteroid.
 26. The pharmaceutical composition ofclaim 19 where the active agent is an antiangiogenic agent.
 27. Thepharmaceutical composition of claim 19 where the active agent is acancer chemotherapeutic agent.
 28. The pharmaceutical composition ofclaim 19 where the active agent is an antibiotic.
 29. The pharmaceuticalcomposition of claim 19 where the active agent is an anti-inflammatoryagent.
 30. A method of treating a disease state treatable by controlledrelease local administration of an active agent, comprising locallyadministering a therapeutically effective amount of the active agent inthe form of a pharmaceutical composition of claim
 19. 31. The method ofclaim 30 where the active agent is selected from anti-infectives,antiseptics, steroids, therapeutic polypeptides, anti-inflammatoryagents, cancer chemotherapeutic agents, narcotics, local anesthetics,antiangiogenic agents, vaccines, antigens, DNA, and antisenseoligonucleotides.
 32. A method of preventing or relieving local pain ata site in a mammal, comprising administering to the site atherapeutically effective amount of a local anesthetic in the form of apharmaceutically acceptable composition of claim 19.